6 I-PRESERVE: Background (ii)The renin angiotensin system (RAS) has a central position in vascular and myocardial remodeling thought to be involved in HF-PEF.Previous trials with RAS inhibitors in this area have not provided overall favorable results although encouraging signals were noted.There is currently no evidence-based treatment to improve patient outcomes.

11 Methods Statistical assumptions:Anticipated annual primary event rate: 18% in the placebo groupExpected reduction in the annual event rate: 14.5 %To provide a statistical power of 90% with a two-sided alpha of 0.05:1440 events needed, requiring 3600 subjects; the estimated recruitment period was 2 years with a follow-up period of 2 yearsDuring the study, based on a blinded assessment of the event rates, the number of subjects was increased to 4100, recruitment to 2.75 years , duration of the study to 6 yearsAlthough the incidence of myocardial infarction is decreasing, the prevalence of AP has changed little and remains high.There are 30 patients with angina for every one with myocardial infarction.As such, angina remains the most common manifestation of CHD and the most common symptomatic cardiac condition.Despite this, relatively little is known about the longterm natural history of angina at a population level, especially in women.Furthermore most existing studies which have reported clinical outcomes have focussed on death or myocardial infarction which gives a misleading perception of the scale of the problem. Patients with angina are likely to be at increased risk of other manifestations of atherosclerosis such as stroke and other complications of CHD such as HF.11

23 I-PRESERVE: ConclusionsThe I-PRESERVE study enrolled a population of older, predominantly female, patients similar to those enrolled in epidemiologic HF-PEF databases.Although this was a well-treated population, they experienced substantial mortality and cardiovascular morbidity.Irbesartan did not reduce the primary endpoint of death and protocol-specified CV hospitalizations, nor did it reduce prespecified secondary endpoints. The medication was well-tolerated.

24 I-PRESERVE: ConclusionsOur results are consistent with the two previous trials utilizing RAS blockers in patients with HF-PEF that did not demonstrate an overall positive effect.For this large group of patients constituting up to half of all heart failure, there continues to be no specific evidence-based therapy.In order for this field to move forward, a better understanding is needed of the mechanisms underlying this syndrome and additional potential targets for treatment.